Phosphorus is critical for bone mineralization, cellular structure, genetic coding, and energy metabolism. Many organic and inorganic forms exist. Phosphorus is present in nearly all foods, and GI absorption of dietary forms is very efficient. Phosphorus homeostasis normally is maintained through several mechanisms (renal excretion, cellular release, hormonal control, etc). When the phosphorus load (from GI absorption, exogenous administration, or cellular release) exceeds renal excretion and tissue uptake, hyperphosphatemia occurs.
Hyperphosphatemia is associated with significant increase in morbidity and mortality, and may induce severe complications, such as hypocalcemia, decreasing of vitamin D production, metastatic calcification. Hyperphosphatemia is also contributing to the increased incidence of cardiovascular disease among dialysis-dependent patients, and can result in bone pathology.
At least 70% of patients with renal insufficiency or renal failure show hyperphosphatemia. In many cases, restricting intake of dietary phosphorus is not sufficient to reduce serum phosphate levels into the normal range, and oral phosphate binders need to be taken.
Calcium and aluminium salts orally taken as treatment for hyperphosphatemia are known. But there are concerns regarding their long-term safety. The traditional aluminium-based phosphate binders have the drawback of side effects due to aluminium absorption (osteomalacia, encephalopathy, microcytic anaemia). Calcium-containing phosphate binders (calcium carbonate or calcium acetate) may aggravate metastatic calcification, particularly if they are taken together with vitamin D analogues and a high calcium dialysate concentration.
An iron-based ferric citrate phosphate binder, known as Zerenex™, is described in U.S. Pat. No. 6,903,235B. Zerenex™ is an oral, inorganic, iron-based compound that has the capacity to bind phosphorous and form non-adsorbable complexes. Since this product is soluble its long term administration may induce an increase of the concentration of iron in gastrointestinal tract, which may be safety issue as mentioned hereinabove.
Sevelamer, a synthetic polymer commercialized by Genzyme under the name of Renagel®, poly(allylamine-co-N,N′-diallyl-1,3-diamino-2-hydroxypropane) hydrochloride is an iron exchange gel matrix.
The phosphate binding capacity of metal oxide hydroxides is known in the art. The possible medical application of metal hydroxides and metal oxide hydroxides as phosphate binders is also described. For example WO9201458 discloses a method of controlling serum phosphate level in patients by iron oxy-hydroxides which bind to ingested phosphate.
For example, U.S. Pat. No. 6,174,442, the content thereof being enclosed herewith by reference, describes an adsorbent for phosphate which contains polynuclear β-iron hydroxide stabilized by carbohydrates and/or humic acid. WO 2006/000547, the content thereof being also enclosed herewith by reference, describes an adsorbent for phosphate which is obtained from iron(III) nitrate or sulfate and is stabilized by starch and sucrose.
The phosphate binding capacity of the known phosphate adsorbents containing oxide hydroxides is limited. Furthermore, the processes described to manufacture such compounds are not suitable for preparing larger amounts of compounds.
The possible release of iron under physiological conditions from any iron containing drugs or compounds, in particular in case of the phosphate adsorbent described in U.S. Pat. No. 6,174,442, may be a safety issue, since excess iron is toxic to body organs. Preferably the daily release of iron should not be higher than 20 mg iron per day. A too high release of iron can particularly problematic in case of patients suffering from haemochromatosis. Haemochromatosis is a very common genetic disorder of iron metabolism wherein absorption of iron through the intestine is uncontrolled even when body saturation levels have been reached.
Furthermore the available phosphate binders and the phosphate adsorbents described in the prior art bind not more than about 120 mg phosphate per gram of product. Because of the relatively low adsorption capacity of these phosphate adsorbents, the amount of adsorbent, e.g. the amount and/or number of oral dosage forms containing it to be taken every day must be high. For example the average daily dosage to be taken by dialysis patients in order to avoid/treat hyperphosphatemia is of about 9 capsules in case of Zerenex™, and of 14 film coated tablets in case of Renagel®. This indicates that the patient compliance of the available phosphate adsorbents is very low.
Due to the high levels of phosphate contained in diet and the relatively low adsorption capacity of the phosphate adsorbents available or described in the prior art, it is necessary to administer such adsorbents in high dose in order to efficiently control the blood level of phosphate. Therefore even a small increase in phosphate binding capacity may permit to decrease the dose of adsorbent to be administered every day, for example to lower the number of oral dosage forms to be administered every day. So even a small increase in phosphate binding capacity would be beneficial to the patient, e.g. would improve patient compliance.
Therefore there is a need to provide a phosphate adsorbent with a high phosphate binding capacity to be usable as a pharmaceutical.
Furthermore there is a need to provide a manufacture process which lead to an adsorbent which is homogenous and stable, and which can be easily formulated and/or packaged, and which can be performed on a large scaling without affecting the properties of the adsorbent, i.e. its phosphate binding capacity.